tbuckley/cabot-search huggingface dataset:
Abstract 2350: Role of ECM hyaluronic acid in the tumor-promoting functions of TIMP-1
Authors: Nithyananda Thorenoor, Wei Xiao, Amyn M. Rojiani, Mumtaz V. Rojiani
Journal: Cancer Research (2023)

Abstract Non-small cell lung carcinoma (NSCLC) is responsible for the most significant number of lung cancer deaths with over 85% of lung cancers falling in this category. The dismal outcomes of this disease are augmented by advanced disease at initial presentation and ongoing development of chemoresistance following standard chemotherapeutic interventions. Tissue Inhibitor of metalloproteinase-1 (TIMP-1), one of the natural inhibitors of matrix degrading enzymes, is classically regarded as a tumor suppressor. However, there is much evidence that has established this molecule as having tumorigenic functions and has been shown to be upregulated in multiple cancers as well as in the development of fibrosis. In earlier studies we have demonstrated the tumor-promoting role of TIMP-1 in multiple biological interactions including angiogenesis, apoptosis, chemoresistance and cancer metabolism in NSCLC. The ECM plays an important role in providing structural support and as a depot for growth factors and cytokines critical for cell signaling. As TIMP-1 remains a vital molecule facilitating and modulating multiple elements of the ECM, we have sought to further define its role in the tumor microenvironment ECM in NSCLC cells. Our investigations have shown that TIMP-1 protein accumulates in the culture medium over long incubation periods. We have also found TIMP1 mRNA upregulation during this incubation period and correlated this as a function of cell density. As high cell density led to increased upregulation of TIMP1 mRNA, we postulated that factors secreted in the culture were responsible for this upregulation. We have identified that hyaluronic acid (HA), a component of the ECM, was accumulating in the culture media, resulting in the above response. HA is a critical matrix molecule of the tumor pericellular stroma and its upregulation is associated with poor prognosis. It is synthesized by hyaluronic acid synthetase (HAS) isoforms 1,2 and 3. We have also found that HAS2 was strongly expressed in high TIMP1 expressing NSCLC cells. Several studies have shown increased HAS2 expression in tumor tissue. We found that knocking down TIMP1 resulted in lower HA levels and decreased expression of HAS2. In a 3D coculture spheroid assay utilizing A549 cells and MRC5, we have shown increased expression of TIMP-1 and HA, which was also confirmed in archived NSCLC patient samples. The role of HA in the tumor-promoting functions of TIMP1 will be discussed further. Citation Format: Nithyananda Thorenoor, Wei Xiao, Amyn M. Rojiani, Mumtaz V. Rojiani. Role of ECM hyaluronic acid in the tumor-promoting functions of TIMP-1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2350.
Abstract 5058: Impact of dexamethasone on chemotherapy response in ovarian cancer
Authors: Annapoorna Venkatachalam, Cristina Correia, Cordelia D. Mcgehee, Sarah Finstuen-Magro, Jamison VanBlaricom, Paula A. Schneider, Kevin L. Peterson, Ethan P. Heinzen, Melissa C. Larson, Xiaonon Hou, Ann L. Oberg, Saravut John Weroha, Scott H. Kaufmann
Journal: Cancer Research (2023)

Abstract Background: Ovarian cancer ranks fifth in cancer deaths among women. The gold standard of care for advanced disease includes cytoreductive surgery along with adjuvant or neoadjuvant platinum/taxane-based chemotherapy. Although response to this treatment is high, chemotherapy-induced nausea and vomiting due to platinum agents and allergic reactions due to both agents are common. For nearly half a century, the glucocorticoid (GC) dexamethasone (DEX) has been administered as part of supportive care. However, there have periodically been questions about the possible deleterious effects of DEX on chemotherapy response, especially in solid tumors. Methods: Platinum-sensitive, glucocorticoid receptor (GRα) expressing ovarian cancer cells were exposed to DEX prior to chemotherapy and clonogenic survival was assessed. The effects of DEX on cell cycle and apoptosis were assessed by flow cytometry. Changes in the tumor cell transcriptome after acute DEX treatment were determined by RNA sequencing. Mice bearing orthotopic ovarian cancer patient-derived xenografts (PDXs) were treated with chemotherapy ± DEX to assess changes in chemotherapy response in vivo. Findings: DEX pre-treatment decreased platinum cytotoxicity in ovarian cancer cell lines in vitro and diminished platinum response in some PDXs analyzed for chemotherapy response ex vivo. RNA-seq analysis revealed changes in transcripts encoding proteins involved in platinum detoxification and TNFα pro-survival signaling. In ovarian cancer PDXs, DEX decreased platinum response in one model and had limited impact on both platinum and platinum/taxane chemotherapy in three distinct studies. Interpretation: DEX appears to modulate chemotherapy response in some settings in vitro and ex-vivo. The impact of DEX on chemotherapy response in vivo appears to be limited. However, further investigation of this question in vivo in non-immunosuppressed murine models appears warranted. Citation Format: Annapoorna Venkatachalam, Cristina Correia, Cordelia D. Mcgehee, Sarah Finstuen-Magro, Jamison VanBlaricom, Paula A. Schneider, Kevin L. Peterson, Ethan P. Heinzen, Melissa C. Larson, Xiaonon Hou, Ann L. Oberg, Saravut John Weroha, Scott H. Kaufmann. Impact of dexamethasone on chemotherapy response in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5058.
Abstract 3099: Hnd-01: a potent inhibitor of wild type mutant BTK
Authors: Jing Zhang, Ahmed A. Samatar, Yue Tan, Shiqing Pi, Zhigang Zhou, Yan Xu, Daihong Yang
Journal: Cancer Research (2023)

Abstract Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinase inhibitor approved for use in patients with chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. Based on the in vitro and in vivo characterization studies of dasatanib, several metabolites were identified. Dasatinib and its metabolite 20 were the major circulating species identified which represented 25.5% and 12.5% of total radioactivity in human plasma respectively. Here, we report the identification of HND-01, a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) which was achieved by modifying metabolite 20 of dasatinib. Bruton’s tyrosine kinase (BTK) is a non-receptor kinase and a key regulator of the B-cell receptor (BCR) signaling pathway. BCR is critical for proliferation and survival of leukemic cells in many B cell malignancies, including chronic lymphocytic leukemia (CLL). BTK is a key target for the development of small molecule inhibitors in B cell malignancies. There are several covalent BTK inhibitors including ibrutinib that have been approved. These covalent inhibitors bind with high affinity to Cys-481 in the active site of BTK. However, some patients develop acquired resistance to ibrutinib due to Cys-481 mutation in the BTK binding site. The acquired resistance to covalent inhibitors can be overcome with the design of new reversible BTK inhibitors. The reversible BTK inhibitors will bind to different sites other than the cysteine residue of BTK and inactivate BTK. These drugs would potentially be active in the presence or absence of the cysteine-to-serine mutation. HND-01, a novel and potent reversible BTK inhibitor inhibits wild type &amp; C481S mutant BTK with IC50 values of 0.157 nM for WTBTK and 0.032 nM for C481SBTK. HND-01 inhibits K562 cell proliferation (IC50 0.183 nM) and it is more stable than dasatinib in human liver microsomes (in vitro clearance; 142 mL/min/kg for HND-01 vs 211 mL/min/kg for dasatinib). In an established human lymphoma efficacy model (TMD-8 model), HND-01 showed stronger tumor inhibition (80.6%) than Ibrutinib (58%). These data demonstrates that HND-01 is a BTK inhibitor that is more potent with potential desirable ADME properties than ibrutinib. HND-01 was filled for international patents, China patent application # 202080030953.6, US patent application #17/636,476, EU application # EP 20853834.8, and Canada application # CA 3148436. Citation Format: Jing Zhang, Ahmed A. Samatar, Yue Tan, Shiqing Pi, Zhigang Zhou, Yan Xu, Daihong Yang. Hnd-01: a potent inhibitor of wild type mutant BTK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3099.
Abstract 4144: Characterization of immune cell phenotypes in patient derived malignant pleural effusion treated with thiostrepton
Authors: Terri Messier, Roxana Del Rio Guerra, George Naumov, Brian Cunniff
Journal: Cancer Research (2023)

Abstract Tumor cells generate elevated levels of reactive oxygen species (ROS) and therefore exhibit increased expression, activity, and reliance on critical ROS scavenging pathways, including the mitochondrial peroxiredoxin 3 (PRX3) system. PRX3 is a critical reactive oxygen species (ROS) scavenging enzyme localized to the mitochondrial matrix. Our group has characterized the mechanism of action of the PRX3 inhibitor and pro-oxidant therapeutic thiostrepton (TS). TS covalently crosslinks the peroxidatic and resolving cysteines of PRX3, leading to increased levels of mitochondrial ROS, resulting in tumor cell death. We have characterized the cellular and chemical composition of malignant pleural effusion (MPE) from patients with advanced cancer and evaluated cellular responses to TS. TS targets PRX3 in both adherent tumor cells and in non-adherent immune cell populations in a dose-dependent manner. We further characterized MPE-infiltrated immune cells and cytokines released following TS-treatment. Together, these data provide the first evidence for the activity of TS in MPE and resulting changes to immune cell profiles. TS is the active pharmaceutical ingredient of RSO-021, a new covalent inhibitor of PRX3 currently being tested in the MITOPE phase 1/2 clinical trial in patients with malignant pleural effusion (MPE) due to advanced solid tumors or malignant mesothelioma (NCT05278975). Citation Format: Terri Messier, Roxana Del Rio Guerra, George Naumov, Brian Cunniff. Characterization of immune cell phenotypes in patient derived malignant pleural effusion treated with thiostrepton. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4144.
Abstract 4815: TMEM9 decreases ER stress-induced misfolded proteins via lysosomal protein degradation
Authors: Dong-Han Wi, Su-Rin Jung, Seong-Ju Lee, Ye-seul Jeon, Youn-Sang Jung, Jae-Il Park
Journal: Cancer Research (2023)

Abstract The endoplasmic reticulum (ER) contributes to various protein modifications such as protein folding. Also, the ER-associated degradation (ERAD) complex removes defective proteins, which prevents the accumulation of misfolded proteins to avoid abnormality of physiological activity. Several physiological and pathological stimuli, such as hypoxia and nutrient starvation lead to unfolded protein responses (UPRs). Given that hyper-proliferation causes hypoxia and glucose shortening, cancer cells might induce UPRs resulting in misfolded protein accumulation and aggregation. Although the ERAD complex removes defective proteins, the capacity of the proteasomal degradation pathway is not enough to completely clear defective proteins in hyper-proliferative cancer cells. Thus, it is likely that cancer cells require additional misfolded protein degradation systems. Transmembrane protein 9 (TMEM9) has been identified as a vesicular acidification amplifier, which is upregulated in cancer cells for Wnt/β-catenin signaling activation via lysosomal protein degradation. In this study, TMEM9 downregulated ER stress-induced misfolded proteins that decrease cancer cell proliferation and viability. ERAD inhibitor declined cancer cell proliferation, reverted by TMEM9. Intriguingly, TMEM9 decreased ERAD-induced apoptosis instead of promoted autophagic cell death under glucose shorten conditions. Here we suggest that lysosomal protein degradation is an additional protein degradation system for the removal of defective proteins and contributes to stable cancer cell proliferation via the clearing of garbage proteins. Citation Format: Dong-Han Wi, Su-Rin Jung, Seong-Ju Lee, Ye-seul Jeon, Youn-Sang Jung, Jae-Il Park. TMEM9 decreases ER stress-induced misfolded proteins via lysosomal protein degradation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4815.
Abstract 3199: Development of a flow cytometry-based assay for measuring specific CAR expression on LGR5-targeting CAR-T cells
Authors: Timona Tyllis, Caitlin Abbott, Dylan McPeake, Jade Foeng, Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli, Stuart Mills, Emma Thompson, Lih Tan, Allison Cowin, Claudine Bonder, Timothy Sadlon, Simon Barry, Shaun McColl
Journal: Cancer Research (2023)

Abstract The measurement of chimeric antigen receptor (CAR) expression is critical for the development, qualification and quantitation of CAR-T cells for clinical applications. There is a comprehensive range of tools commercially available for specifically measuring expression of the CAR on CD19-targeting CAR-T cells. However, with the rapidly expanding repertoire of CAR-T cells in development targeting a diverse range of tumour antigens, there is a paucity of readily implementable assays that specifically measure CAR expression, which is essential for translation into the clinic. We have developed several CARs targeting the cancer stem cell marker LGR5, one of which (CNA3103) is the lead candidate in an upcoming clinical trial in advanced metastatic colorectal cancer. Previously, the level of CNA3103 expression in this system has been determined indirectly by measuring expression of tEGFR on the CAR-T cell surface, taking advantage of co-expression of the CAR and tEGFR upon transduction with our lentiviral construct. tEGFR expression was found over many CAR-T cell manufacturing batches to report transduction efficiency reproducibly with high sensitivity. However, to specifically quantify expression of the CNA3103, an assay utilising an Fc-tagged recombinant human LGR5 protein, in combination with an anti-human IgG1 Fc-specific secondary antibody was developed. A number of optimisation steps including titration of multiple batches of rhLGR5-Fc, different anti-human IgG1 Fc-specific antibodies and a range of incubation parameters were tested. This resulted in development of an assay that yielded very similar reproducibility and sensitivity to that previously observed with the indirect tEGFR surrogate assay. Overall, the findings highlight the utility of using CAR-targeting recombinant proteins for evaluating CAR expression on CAR-T cells, providing a general flow cytometry-based staining strategy that may be adapted for assessing a diverse repertoire of CARs. Citation Format: Timona Tyllis, Caitlin Abbott, Dylan McPeake, Jade Foeng, Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli, Stuart Mills, Emma Thompson, Lih Tan, Allison Cowin, Claudine Bonder, Timothy Sadlon, Simon Barry, Shaun McColl. Development of a flow cytometry-based assay for measuring specific CAR expression on LGR5-targeting CAR-T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3199.
Abstract 2165: Identification and characterization of Karyopherin α2 (KPNA2), a member of the nucleocytoplasmic transporter family, in lung cancer
Authors: Seoree Kim, Heejin Lee, Jung-Sook Yoon, Hyun Woo Lee, Seok Yun Kang, Ji Hyun Lee, Sang Hoon Chun, Hye Sung Won, Soon Auck Hong, Keunsoo Kang, Young-Ho Ahn, Yoon Ho Ko
Journal: Cancer Research (2023)

Abstract Introduction: Many oncologists began to make sense, that the Karyopherin a-2 (KPNA2), a nucleocytoplasmic transport protein, regulates the nuclear import of macromolecules and changes in cellular phenotype. In particular, it can be a poor prognostic marker by causing aberrant subcellular localization of DNA damage response proteins or OCT4-c MYC pathway molecules depending on the type of carcinoma. An association with the p53 oncogenic pathway has been reported, showing good prognostic values in other types. We aimed to investigate the clinical significance and metabolic pathway of stable CAF and cancer cells for KPNA2 Method: We retrospectively analyzed the data from NSCLC patients receiving curative resection in Uijeongbu and Bucheon St. Mary’s Hospitals (n=165). IHC staining was performed on the tumor microarray samples using antibodies against KPNA2. The positivity was defined as median value of H-score. Result: Based on the TMA staining, mean KPNA2 score was 36.5 [0-240] and median value was 10. Table 1. Scatter plots and correlation between KPNA2 expression levels and tumor invasiveness markers reveals that high KPNA2 expressor was related to lymphatic invasion (p = 0.00782), advanced stage (p = 0.0202) and current smoker (p = 0.0074). KPNA2 expression was higher in squamous cell carcinoma(SqCC) histotype than in adenocarcinoma (SqCC ratio (%), 13.5 vs 43.4 in Low exp vs High exp; p = 0.007). Patients with high expression of KPNA2 showed shorter survival than other patients (median OS (mo), 72.8 vs 42.2, P &amp;lt; 0.0001; median RFS (mo), 72.8 vs 32.1, P &amp;lt; 0.0011) and relevant to high recurrence (recurrence rate (%), 24.7 vs 44.7, p = 0.007). Conclusion: Taken together, our results suggest that KPNA2 protein expression has a poor prognostic association, revealed by its association with survival outcome or invasiveness markers. Its clinical significance as an oncogenic target molecule is emerging, and further evaluation using an organoid model is in progress. Baseline clinical and pathological characteristics Citation Format: Seoree Kim, Heejin Lee, Jung-Sook Yoon, Hyun Woo Lee, Seok Yun Kang, Ji Hyun Lee, Sang Hoon Chun, Hye Sung Won, Soon Auck Hong, Keunsoo Kang, Young-Ho Ahn, Yoon Ho Ko. Identification and characterization of Karyopherin α2 (KPNA2), a member of the nucleocytoplasmic transporter family, in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2165.
Abstract 273: Synergistically suppressive effects by combination of glycolytic inhibitor with TRAP1-depletion in colorectal cancer
Authors: Hong-Yuan Tsai, Miao-Hsueh Chen, Herath Lakmini Senavirathna, Jihye Yun, Sheng Pan, Ru Chen
Journal: Cancer Research (2023)

Abstract Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial homolog of HSP90 chaperones. It plays an important role in protection against oxidative stress and apoptosis by regulating reactive oxidative species (ROS). Recent studies have suggested TRAP1 as a regulator of metabolism and mitochondrial homeostasis in diverse pathological states, including cancer. To further elucidate the mechanistic role of TRAP1 in regulating tumor cell survival, we used gamitrinib-triphenylphosphonium (G-TPP) to inhibit TRAP1 signaling pathways in colon cancer. Inhibition of TRAP1 disrupted redox homeostasis and increased ER stress in colon cancer. To confirm the G-TPP effects of TRAP1 inhibition in colon cancer, we performed TRAP1 CRISPR/Cas9 to deplete TRAP1 expression in colon cancer cell line CT26. TRAP1-depleted cells were found to acquire several distinct phenotypes: induction of reactive oxidative species (ROS) level, reduction of cell growth, and lower pH value of culture medium. In addition, proteomic data showed that depletion of TRAP1 induced significant metabolism alteration in CT26 cells. Using seahorse assay to access mitochondrial respiration and glycolysis, we found that TRAP1-depleted cells were insensitive to Oxidative Phosphorylation (OXPHOS) inhibitor treatment and significantly increased extracellular acidification rate (ECAR) compared to parental cells. Furthermore, higher glucose consumption rate and higher lactic acid level of culture medium were observed in TRAP1-depleted cells. On the other hand, Glycolytic inhibitor (2DG) led to excessive ROS production, reduction of glucose uptake and exacerbated cell death in TRAP1-depleted cell compared to parental cells. Taken together, depletion of TRAP1 induces mitochondrial dysfunction and modulates metabolic switch toward aerobic glycolysis in TRAP1-depleted colon cancer cells. Dual inhibition of TRAP1 and glycolytic signaling may increase therapeutic efficiency through induction of excessive ROS production in colon cancer. Citation Format: Hong-Yuan Tsai, Miao-Hsueh Chen, Herath Lakmini Senavirathna, Jihye Yun, Sheng Pan, Ru Chen. Synergistically suppressive effects by combination of glycolytic inhibitor with TRAP1-depletion in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 273.
Abstract 5145: Targeting TREX1 induces innate immune response in chemoresistant small cell lung cancer
Authors: Takahiko Murayama, Navin R. Mahadevan, Tetsuo Tani, Xueying Ma, Hideo Watanabe, David A. Barbie, Israel Cañadas
Journal: Cancer Research (2023)

Abstract Small cell lung cancer (SCLC) is the most lethal type of lung cancer. The uniqueness of this tumor consists of an initial exquisite response to chemotherapy. However, at relapse, which occurs nearly in all patients, the tumor is resistant to all available therapies, causing a premature death of the patient. Despite the addition of immune checkpoint blockade (ICB) therapy to standard chemotherapy, response rates are modest and only a very small fraction of SCLC patients responds to these therapies. The mechanistic basis for acquired chemoresistance and impaired immunogenicity in SCLC remains to be elucidated. Here, we report that the expression of three prime repair exonuclease 1 (TREX1) is strongly induced in chemoresistant SCLCs. ATAC-seq and ChIP-seq analyses revealed a significant increase in chromatin accessibility of TREX1 gene locus in drug resistant SCLC cells. Depletion of TREX1 in SCLC cells caused the activation of cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway due to the cytoplasmic accumulation of DNA damage-associated double-stranded DNA (dsDNA) and micronuclei. Furthermore, targeting TREX1 induced an innate immune response and re-sensitized chemoresistant SCLC cells to chemotherapy. These findings suggest that TREX1 upregulation may be an important mediator of cGAS/STING pathway inactivation in cancer, contributing to the survival of resistant cells, and its inhibition may represent a promising therapeutic strategy to potentiate the efficacy of chemotherapy and immunotherapy in chemoresistant and immunologically ‘cold’ tumors, such as SCLC. Citation Format: Takahiko Murayama, Navin R. Mahadevan, Tetsuo Tani, Xueying Ma, Hideo Watanabe, David A. Barbie, Israel Cañadas. Targeting TREX1 induces innate immune response in chemoresistant small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5145.